Dihexa

Mechanism (as reported)

Research described in the sources indicates that dihexa binds with high affinity to hepatocyte growth factor (HGF), induces c-Met phosphorylation, and promotes HGF-dependent cell scattering; these effects were reported to be inhibited by an HGF antagonist and by c-Met knockdown. The same study reported that dihexa and its parent AngIV-related compound induced hippocampal spinogenesis and synaptogenesis similar to HGF itself, and that blocking HGF reduced dihexa’s procognitive effect in a Morris water maze learning task. Additional review sources describe the HGF/c-Met receptor system as a target associated with synaptogenesis and neurogenesis, and relate dihexa to this pathway.

Key findings (each cites a source)

• A study reported that dihexa is an orally active, blood-brain barrier–permeable analog of an AngIV-related molecule and investigated its procognitive mechanism. [PMID 25187433]
• A study reported that dihexa binds with high affinity to hepatocyte growth factor (HGF) and that dihexa (and its parent compound Norleucine 1-AngIV) induced c-Met phosphorylation and augmented HGF-dependent cell scattering. [PMID 25187433]
• A study reported that dihexa and Norleucine 1-AngIV induced hippocampal spinogenesis and synaptogenesis similar to HGF, and that these actions were inhibited by an HGF antagonist and by c-Met knockdown. [PMID 25187433]
• A study reported that blocking HGF (using an HGF antagonist delivered intracerebroventricularly) blocked the procognitive/antidementia capacity of orally delivered dihexa in the Morris water maze spatial learning task. [PMID 25187433]
• A review summarized information linking the HGF/c-Met receptor system to Alzheimer’s disease treatment approaches, and stated that stimulation by an angiotensin-based analogue Dihexa induced dendritic arborization and synaptogenesis and was associated with memory facilitation in animal models. [PMID 25649658]
• A systematic review reported that in experimental (non-human) studies, AngIV and AngIV analogs (including dihexa) were associated with improved performance on spatial working memory and passive avoidance tasks in cognitive deficit models. [PMID 29733881]
• A study described chemical modification of an AngIV analog to produce a metabolically stabilized, orally active, blood-barrier permeant analog (dihexa) and reported antidementia activity in scopolamine and aged rat models as well as marked synaptogenic activity. [PMID 23055539]
• A review reported development of small-molecule AngIV analogs aimed at Alzheimer’s and Parkinson’s diseases and described dihexa as showing promise by augmenting synaptic connectivity via formation of new functional synapses. [PMID 25455861]
• A small-molecule strategy study reported that combining Vitamin C, Dihexa, and Forskolin (VDF) could substitute growth factors to induce hepatic specification from human pluripotent stem cells, leading to hepatoblast formation and functional hepatocyte-like cells in vitro and functional behavior described in vivo. [PMID 35410439]
• A review on orthopaedic therapeutic peptides mentioned neuroactive peptides such as dihexa and described them as targeting brain-derived neurotrophic factor and HGF/c-Met pathways relevant to neuroplasticity (as presented in that review). [PMID 41490200]
• A study on radiolabeled dimeric alpha-MSH analogs included dimeric peptide constructs containing a “diHexa” motif and reported that although the dimers showed increased receptor affinity and excellent internalization in vitro, tumor-to-kidney ratios in vivo were less favorable compared with a monomeric standard, with marked kidney uptake described as an unfavorable factor. [PMID 18097939]